Modern flow chemistry – prospect and advantage

We report the high-speed C–H chlorination of ethylene carbonate, which gives chloroethylene carbonate, a precursor to vinylene carbonate. A novel photoflow setup designed for a gas–liquid biphasic reaction turned out to be useful for the direct use of chlorine gas. The setup employed sloped channels so as to make the liquid phase thinner, ensuring a high surface-to-volume ratio. When ethylene carbonate was introduced to the reactor, the residence time was measured to be 15 or 30 s, depending on the slope of the reactor set at 15 or 5°, respectively. Such short time of exposition sufficed the photo C–H chlorination. The partial irradiation of the flow channels also sufficed for the C–H chlorination, which is consistent with the requirement of photoirradiation for the purpose of radical initiation. Near-complete selectivity for single chlorination required the low conversion of ethylene carbonate such as 9%, which was controlled by limited introduction of chlorine gas. At a higher conversion of ethylene carbonate such as 61%, the selectivity for monochlorinated ethylene carbonate over dichlorinated ethylene carbonate was 86%. We found that the substrate contamination with water negatively influenced the performance of the C–H chlorination. Introduction The C–H chlorination by molecular chlorine is a highly exothermic reaction that proceeds via a radical chain mechanism as illustrated in Scheme 1 [1-6]. Frequently, photoirradiation is used for radical initiation through homolysis of the Cl–Cl bond to generate chlorine radicals. In a subsequent step, a SH2 reaction by chlorine radicals at C–H bonds generates alkyl radicals Beilstein J. Org. Chem. 2022, 18, 152–158. 153 and HCl. The second SH2 reaction between alkyl radicals and molecular chlorine then occurs to give the C–H chlorinated product and a chlorine radical, sustaining the radical chain. Chlorine gas is a cheap feedstock since it is formed as a byproduct of the electrolysis of NaCl to produce NaOH in an industrial process [7]. We felt that C–H chlorination would be updated by using scalable flash chemistry [8]. Scheme 1: Radical chain mechanism for a photo-induced C–H chlorination reaction. Flow C–H chlorination using a compact flow reactor is highly desirable in terms of efficiency and safety in handling highly toxic gases such as chlorine. In 2002, Jähnisch and co-workers reported the first microflow chlorination of 2,4-diisocyano-1methylbenzene, which used a falling-film reactor developed by IMM [9]. While the flow rate employed was quite low (0.12 mL/min of toluene), the residence time was less than 14 seconds. More recent studies on flow C–H chlorination reactions focused on the use of Cl2 gas in situ generated by photolysis of sulfuryl chloride [10] or by acid treatment of NaOCl [11,12]. We thought that if rationally designed scalable photoflow setups were available, flow C–H chlorination reactions using chlorine gas would be able to focus on production. In this study, we tested a novel photoflow setup consisting of quartz-made straight-line reactors, which are provided from MiChS (LX-1, Figure 1a) and a high-power LED (MiChS LED-s, 365 ± 5 nm, Figure 1b) [13]. Each channel track has a 2 mm depth and 557 mm length, while the width varies from 6 or 13 mm depending on the number of channels 7 or 5, respectively. The flow photoreactor is embedded into an aluminum frame equipped with a heat carrier channel. The design concepts including angle settings to ensure a thin liquid layer are summarized in Figure 1. We chose the C–H chlorination of ethylene carbonate (1) as a model reaction (Scheme 2). Chlorinated ethylene carbonate 2 is a precursor to vinylene carbonate (3), which is used as an electrolyte additive for Li-ion batteries [14-20]. Vinylene carbonate also serves as a useful synthetic building block for Diels–Alder reactions [21-25] and polymerization [26-30]. Results and Discussion Using a PTFE tube and PTFE connectors, we connected the photoflow setup with a chlorine gas cylinder through a floating gas level meter in a fume hood (Figure 2). Since ethylene carbonate (1) melts between 34–37 °C, we preheated the container of 1 using an oil bath at 70 °C and pumped it to the photoreactor. In the reactor, hot water (80 °C) was circulated through a hole channel manufactured in an aluminum-made frame to keep the contacted glass reactor warm. The LED lamp was placed on the upper side of the reactor with a 20° angle to the reactor surface. The exiting gases (HCl and unreacted Cl2) were trapped by an aqueous NaOH solution (1.7 M). The reactors are set with a slope of 15 or 5° to achieve a thin substrate layer causing a rapid gas/liquid biphasic reaction. The residence time was estimated to be 15 and 30 seconds, respectively (for the measurement, ethylene carbonate was introduced in the absence of chlorine gas). After the experiments, chlorine gas that remained inside the flow setup was flushed with N2 gas. In general, we used ethylene carbonate (1) with the grade containing less than 0.03% of water. The results are summarized in Table 1. When the reaction of ethylene carbonate (1, flow rate: 74.9 mmol/min, containing 0.03% of H2O) with 0.17 equiv of Cl2 gas (flow rate: 12.5 mmol/min) was carried out under irradiation by UV-LED (240 W) with a 15° reactor angle, the desired chloroethylene carbonate (2) was formed selectively with a 9% conversion of 1 (Table 1, entry 1). When 0.23 equiv of Cl2 was used, the selectivity became 96% with 12% conversion of 1, in which a small amount of undesired 1,2-dichloroethylene carbonate (2’) was detected by GC (Table 1, entry 2). When 0.45 equiv of Cl2 was used, the conversion of 1 increased to 21% and the selectivity of 2 became 91% (Table 1, entry 3). The reaction of 1 with one equivalent of Cl2 gave 2 and 2’ in a ratio of 89:11 with 39% conversion of 1 (Table 1, entry 4). When the reaction mixture was circulated twice, we observed a higher conversion of 1 (87%) and obtained a 74:26 mixture of 2 and 2’ (Table 1, entry 5). Then, we limited the feeding of 1 (flow rate: 46.4 mmol/min) in order to increase conversion, which worked well. The reaction of 1 with 1.97 equiv of Cl2 resulted in 61% conversion of 1 and an 86:14 ratio of 2 and 2’ (Table 1, entry 6). When a lower feeding of 1 (29.6 mmol/min) and an excess amount of Cl2 (3.09 equiv) were used, higher conversion of 1 (76%) was attained with the selectivity of 84:16 (Table 1, entry 7). The irradiation at 600 W gave an almost similar result (Table 1, entries 8 and 9), which suggested that 240 W sufficed the reaction. Indeed, when the reaction was Beilstein J. Org. Chem. 2022, 18, 152–158. 154 Figure 1: Components for photoflow setup: (a) MiChS LX-1 reactor and (b) MiChS LED-s (365 ± 5 nm, 60–600 W). carried out with a shallow reactor angle such as 5°, the conversion of 1 increased from 49 to 61% (Table 1, entries 8 and 10). This is due to the extended residence time from 15 to 30 s. Flow gas/liquid reactions are often carried out using a tubular reactor and mixer under slug flow conditions. However, it is not easy to apply such conditions to the present photochlorination reaction since the volume of the Cl2 gas is ca. 400 times larger than that of ethylene carbonate (for entry 8 in Table 1). In addition, a much longer tubular reactor would be required to ensure 15–30 s residence time. Beilstein J. Org. Chem. 2022, 18, 152–158. 155 Scheme 2: Model reaction: photoflow C–H chlorination of ethylene carbonate (1) to chloroethylene carbonate (2). Figure 2: Photoflow setup for the C–H chlorination of ethylene carbonate (1). Beilstein J. Org. Chem. 2022, 18, 152–158. 156 Table 1: Photoflow C–H chlorination of ethylene carbonate (1) to chloroethylene carbonate (2).a entry angle (°) flow rate UV-LED (W) conversion (%)b selectivity (%)b 1a (mmol/min) Cl2 (mmol/min) (equiv) 2 2’ 1 15 74.9 12.5 (0.17) 240 9 100 0 2 15 74.9 17.4 (0.23) 240 12 96 4 3 15 74.9 33.9 (0.45) 240 21 91 9 4 15 74.9 75.9 (1.01) 240 39 89 11 5c 15 74.9 75.9 + 75.9 (2.02) 240 87 74 26 6 15 46.4 91.5 (1.97) 240 61 86 14 7 15 29.6 91.5 (3.09) 240 76 84 16 8 15 117.6 146.5 (1.25) 240 49 78 22 9 15 117.6 143.7 (1.22) 600 47 78 22 10 5 117.6 146.5 (1.25) 240 61 79 21 aReactions were conducted by using LX-1 with a reactor angle of 15° or 5° (entry 10). Photoirradiation was carried out by using LEDs (365 ± 5 nm at the power of 240 or 600 W). Ethylene carbonate (1) contains 0.03% of H2O. bDetermined by GC analysis. cReaction mixture was circulated twice. Table 2: Effect of contamination of water.a entry water contamination flow rate conversion (%)b selectivity (%)b 1a (mmol/min) Cl2 (mmol/min) (equiv) 2 2’ 1 0.03% 187.0 126.8 (0.68) 26 96 4 2 0.15% 187.0 112.7 (0.60) 11 92 8 3 0.76% 187.0 118.3 (0.63) 9 100 0 aReactions were conducted by using LX-1 with a rector angle of 15° and LEDs (240 W). bMeasured by GC. We then investigated the effect of contamination with water on the reaction, since Cl2 gas is known to react with H2O under irradiation conditions [31] and the results are summarized in Table 2. The flow rate of 1 and the equivalents of chlorine to 1 were set to be 187 mmol/min and 0.60–0.69, respectively. The reactor angle and light power were 15° and 240 W, respectively. The chlorination reaction using an ordinary grade of the substrate 1 containing 0.03% of water gave a 96:4 ratio of products 2 and 2’ with 26% conversion of 1 (Table 2, entry 1). In contrast, when we used substrate 1 containing 0.15% of water, the conversion decreased to 11% (Table 2, entry 2). With 0.76% of water, the conversion decreased further to 9% (Table 2, entry 3). These results suggest that the reaction has to be carried out carefully under dry conditions. Conclusion In this work, we reported that a novel photoflow setup designed for a gas–liquid biphasic reaction turned out to be useful for the C–H chlorination using chlorine gas in flow. Two decades after the first report on the microflow chlorination of a toluene derivative by Jähnisch and co-workers, we propose a new photoflow setup for C–H chlorination using chlorine gas, applicable to scalable flow C–H chlorination. In our test reaction using C–H chlorination of ethylene carbonate (1), chloroethylene carbonate (2) was obtained in good to excellent selectivity by tuning the flow rates of 1 and chlorine gas. Partial irradiation of the flow channel is sufficient for the C–H chlorination, consistent with the requirement for light irradiation for the radical initiation step. If we apply the conditions to give 80% selectivity with 60% conversion with 30 s residence time, around 15 kilograms of chloroethylene carbonate (2) can be synthesized per day, which suggests the high potential of the present photoflow setup. We also demonstrated that the contamination with water had a negative impact on the reaction and the system should be kept dry for continuous production. We are now investigating some other photo gas–liquid flow reactions, which will be reported in due course. Experimental The photoflow setup consisting of a flow photoreactor LX-1 and UV-LEDs were supplied from MiChS Inc., Ltd. (http://www.michs.jp). The angle of the photoflow reactor was set to be 15 or 5° and heated water at 80 °C was circulated in a channel of an aluminum-made frame to avoid solidification of Beilstein J. Org. Chem. 2022, 18, 152–158. 157 ethylene carbonate (1), whose melting point is 34–37 oC. The UV-LED (365 ± 5 nm) was set with an angle of 20° to the reactor surface. Ethylene carbonate (1) preheated to 70 °C was fed into each channel of the flow photoreactor by using a diaphragm pump. At the same time, chlorine gas was fed into the reactor from the top-side inlet. Evolved HCl gas and unreacted Cl2 gas were trapped by an aqueous 1.7 M NaOH solution. The first eluted solution was discarded for 3 min after which the eluted solution was collected for analysis. GC analysis was performed on a Shimadzu GC-2014 equipped with an FID detector using an Agilent J&W DB-1 column (Ø 0.25 mm × 30 m) under the following conditions: initial oven temperature: 40 °C, temperature change rate of 5 °C/min to 250 °C, hold at this temperature for 10 min. Yields were determined by using the percentage peak area method with compensation for the relative sensitivities of each component. Product 2 and byproduct 2’ were confirmed by 1H and 13C NMR analysis (see Supporting Information File 1). Supporting Information Supporting Information File 1 GC analysis and NMR spectra of the crude reaction mixture for the chlorination of compound 1. [https://www.beilstein-journals.org/bjoc/content/ supplementary/1860-5397-18-16-S1.pdf] Acknowledgements We thank Prof. Masaaki Sato and Dr. Hitoshi Mitsui at MiChS Inc. for useful discussions. IR thanks the Center for Emergent Functional Matter Science at NYCU for support.

Organic chemistry has shaped modern society by fulfilling the basic needs for pharmaceuticals, agrochemicals, fragrances, and many more. Implementation of new and innovative technologies has played a vital role in this mission and has contributed to the opening of new research areas and to pushing the frontiers of existing ones. Among these new technologies, continuous flow chemistry has stepped on the stage in the last decades [1]. Originating from the petrochemical industry, where it enabled high productivity and scalability even for the most standard processes of heating, cracking, and refining of crude oil to bulk chemicals [2], it has since entered the production of pharmaceuticals and other fine chemicals. This has again led to improved scalability, higher purity of products, and eventually decreased manufacturing costs.
From the undisputed role of continuous flow chemistry for process chemists, the advent of this technology in academic research laboratories, especially for method development and natural product synthesis programs [3], has revealed some inadequacies, particularly in view of the equipment and procedures available. These limitations have been slowly over-come with many creative but sometimes highly "academic" solutions.
Thus, recent years witnessed a steady increase in the application of continuous flow technology for academic research, leading to an expansion of synthetic options and generally more sustainable operations. Among the many advantages of performing organic reactions in continuous flow, enhanced heat-, mass-and photon transfer, an improved safety profile, broad scalability, and higher sustainability are the most prevalent ones.
To provide examples and explanation for these claims, "flash chemistry", a term coined by late Yoshida [4] for reactions at the diffusion limit, i.e., reactions completed within milliseconds with proper mixing, showcases the fast heat-and mass transfer of continuous flow reactors. The generation of organolithium species in the presence of carbonyl compounds and their reaction has been facilitated by the extremely fast mixing of reagents and almost instantaneous heat transfer (i.e., cooling) in specifically designed microreactors [5].
Analogously, significantly increased photon transfer in flow reactors has been exploited. Where the molar attenuation coefficient is high, such as in many important photoredox catalysts, most of the irradiation is already absorbed within a thin layer of a few millimeters. Thus, in batch reactors the vast volume of the solution is not irradiated, and the reaction can only take place in the outermost layer [6,7]. This results in an extended reaction time when performing such reactions in bulk and may even lead to increased side reactions. Moving such operations into tubular flow reactors with a small diameter can both accelerate the transformations as well as lead to significantly less side products by continuously removing the products from the irradiation source.
As an example, Noël and co-workers performed efficient irradiation in flow for the C(sp 3 )-H functionalization of gaseous hydrocarbons [8], wherein photoexcited decatungstate was employed. Decatungstate is an efficient and versatile hydrogen atom transfer (HAT) catalyst with a growing number of applications. The use of decatungstate in a continuous flow setup led to shorter reaction times, increased scalability, and improved safety with pressurized gaseous alkanes employed in the abovementioned transformations.
Enhanced safety profiles of continuous flow reactors have been widely appreciated in industrial laboratories, while hazardous reactions still tend to be addressed subordinately or are even marginalized in academia [9]. The comparably small dimensions of flow reactors enable explosive, toxic, or otherwise dangerous reactions and reagents to be accumulated only to a much lesser degree, especially when scaling up. This virtue has been exploited in process chemistry, where in the manufacturing of HIV protease inhibitor nelfinavir mesylate, diazomethane was an inevitable necessity. By moving the generation of this toxic and explosive reagent into a continuous process with manageable amounts present at any given point and continuously stripping the chemical with a stream of nitrogen, safety protocols could be met [10].
Among the disadvantages when moving from batch reactions to a continuous flow regime, dispersion phenomena play a detrimental role. These gradient effects occur when a stream of reagent is introduced into the reactor by pushing it with pure solvent. The reagents with well-defined concentration then leach into the solvent slug, leading to ill-defined stoichiometry and decrease in yield. While this axial dispersion is dependent on flow speed and residence time, only the central part of the reaction stream is under so-called steady-state conditions. To zero out these effects when a process yield is to be determined, pre-and postrun fractions are discarded [6], leading to loss of reagent and substrate as well as to increased waste. This is even less tolerable when small quantities of precious intermediates from multistep routes are to be employed, as is typically the case in projects of the pharmaceutical industry and academia.
A possible solution to this general problem was reported by Jensen and co-workers, who introduced segmented gas-liquid flow by mixing the reagent stream with an inert carrier gas, forming liquid and gaseous slugs moving through the reactor, and thus insolating liquid compartments from leaching into one another [11]. This concept has been adapted and further refined by Gilmore and co-workers, introducing automated multistep synthesizers [12], as well as Heretsch et al. in a setup optimized for natural products synthesis and late-stage manipulations [13].
To address customized reactor solutions from an engineering perspective, the advent of computer-aided design (CAD) in combination with widely available 3D printing has become a preferred choice. Prototyping aided by these technologies has significantly accelerated the development of novel flow reactor designs [14]. The challenging properties of organic solvents for standard polymers used in commercial 3D printers remain a drawback, while industrial 3D printers remain the much more expensive option. Reactors or other laboratory ware printed in polypropylene are restricted in use to only a few organic solvents or even to a single application, rendering this technology rather a supportive tool than a general solution [15]. Still, having this option available significantly lowers the barrier of inventing novel technological solutions and allows for highthroughput optimization in reactor design. Since different types of reactions typically call for an optimized or even specifically designed reactor built, the modularity of flow reactor is vital for quick reconfiguration and switching between different reactions.
This argument is particularly true when natural product synthesis is to be performed in continuous flow. The need for flexible and modular reactors that address the different demands associated with total synthesis poses particular challenges, among them performing fast reactions at low temperature, slow reactions at elevated temperature, reactions involving reactive gases under pressure, and photochemical reactions. Besides, also scalability is a major prerequisite in these synthetic endeavors, with reactions routinely being performed on a decagram scale in the early stages of a route and on a milligram scale at the end of a sequence. Designing modular reactors that meet these demands will help to overcome existing reservations for continuous flow in academia [13].
As guest editor of this thematic issue, I would like to express my gratitude to all authors for their excellent contributions. I thank the referees for providing their expertise and time and the whole team at the Beilstein Journal of Organic Chemistry for their professional support.